Development of a Th17-Inducing Dendritic Cell Vaccine for Ovarian Cancer
In this research project, Mayo Clinic Ovarian Cancer SPORE investigators aim to assess if induction of Th17 immune responses targeting ovarian cancer will overcome tumor immune suppression.
Leaders of this research project and other investigators have already shown that the ability of ovarian cancer to evade host immune responses is due in large part to the influence of regulatory T cells (Tregs). These are CD4+ T cells that cause anergy of ovarian cancer-reactive T helper 1 (Th1) and CD8+ T cells and immunosuppressive changes in macrophages and dendritic cells (DCs).
Tregs are induced during both endogenous anti-ovarian cancer immune responses and in the context of anti-ovarian cancer vaccines, thereby limiting vaccine efficacy. However, the presence of T helper 17 (Th17) cells promotes a proinflammatory antigen-specific immune response and is associated with reduced levels of Tregs.
Our project team has described a novel strategy of ex vivo dendritic cell maturation that leads to a robust antigen-specific Th17 response.
In a murine model of ovarian cancer, Th17-inducing dendritic cells stimulated anti-ovarian cancer Th17 immune responses, a dramatic reduction in Tregs and durable ovarian cancer remissions. In parallel studies, our team also identified a novel ovarian cancer antigen, folate receptor alpha (FRα), that is overexpressed on the vast majority of human (and mouse) ovarian cancer tumors and is associated with worse clinical outcomes.
Our investigators have identified antigenic peptides from FRα, and a clinical study testing these peptides in a therapeutic vaccine has been completed.
Building on these results, our project team proposes to:
- Determine the immune effectors underpinning the anti-tumor efficacy of Th17-inducing cancer vaccines
- Assess whether induction of Th17 immune responses targeting ovarian cancer antigens will overcome local tumor immune suppression by inhibiting Treg generation and modulating infiltrating myeloid cell function
In addition, investigators plan to complete a vaccine therapy clinical trial to determine whether FRα-specific Th17 T cell responses can be safely generated in patients with ovarian cancer after adjuvant chemotherapy. This trial is being performed in the setting of minimal residual disease, where immunotherapy might be most effective.